MIF is a regulator of inflammation and innate, as well as adaptive, immune responses. However, current research suggests an even greater role for MIF, as it is present in a variety of immune and non-immune cells (Baugh et al., Crit. Care Med. 30: Suppl. S27-S35, 2002). MIF is constitutively expressed in tissues such as the anterior pituitary, prostate epithelia (Meyer-Siegler et al., Diag. Mol. Path. 7:44-50, 1998; and Meyer-Siegler, Cytokine 12:914-921, 2000), gastric, small intestinal and colonic epithelia (Maaser et al., Gastroenterology 122:667-680, 2002), neuronal and non-neuronal cells in the brain (Bacher et al., Mol. Med. 4:217-230, 1998).
As a proinflammatory cytokine, MIF counter-regulates the effects of glucocorticoids (Baugh et al., Crit. Care Med. 30: Suppl. S27-S35, 2002; and Lue et al., Microbes and Infection 4:449-460, 2002). Therefore, MIF has been proposed to play a critical role in immune and inflammatory diseases including septic shock (Bernhagen et al., Nature 365:756-793, 1993), rheumatoid arthritis (Leech et al., Arthritis & Rheumatism 42:1601-1608, 1999), delayed-type hypersensitivity (Brown et al., Transplantation 71:1777-1783, 2001), Crohn's disease (De Jong et al., Nature Immunology 2:1061-1066, 2001), gastric ulcer formation (Vera et al., Brain Res. Bulletin 29:651-658, 1992), and prostate cancer (Meyer-Siegler et al., Diag. Mol. Path. 7:44-50, 1998; and Meyer-Siegler, Cytokine 12:914-921, 2000). Treatment with anti-MIF antibodies has been reported to prevent experimental colitis and treat established colitis in experimental animals (De Jong et al., Nature Immunology 2:1061-1066, 2001). Therefore, anti-MIF therapy might represent a potentially useful therapeutic tool in the treatment of different inflammatory conditions.
As a new and novel finding we have determined that the urothelium is a rich source of pre-formed MIF. MIF is released from the bladder epithelium upon induction of inflammation and inactivation of released MIF by intravesical anti-MIF antibody reduces inflammation in the bladder, prostate and the spinal cord. These results suggest that this knowledge may have commercial application.
MIF was first described thirty years ago and was designated as a cytokine, a chemical mediator, which regulates cell growth by inducing the expression of specific target genes. The initial described function of MIF was as a regulator of inflammation and immunity. It is expressed in the brain, and eye lens, is a delayed early response gene in fibroblasts, and it has been reported that this protein can be found in prostate tissues. MIF has been shown to be a pituitary, as well as macrophage cytokine and a critical mediator of septic shock. Recent studies also suggest that MIF may have an autocrine function for embryo development and is produced by the Leydig cells of the testes. Thus, it appears that this cytokine may play a fundamental role in cell growth regulation and possibly development.
U.S. Pat. No. 6,043,044 discloses the use of prostate tissue extracts as a patient sample to determine the amount of MIF. Immuno- and RNA blot analysis performed using homogenized tissue that contains variable proportions of epithelial and stromal cells still determined significant differences in the levels of MIF protein produced by metastatic tissue (490.3+/−71.3 ng/mg total protein). In practice this test was unreliable and difficult to perform because of contamination with surrounding connective and stromal tissue. It does not have utility in patient diagnosis or prognosis. Further, the patent does not mention or correlate urine, bladder tissue, and/or prostate tissue MIF levels with urological inflammatory disease. Therefore, a need exists for an improved assay with commercial application that is less invasive than that of the prior art.